Prostate cancer is the most frequently diagnosed solid tumor in men, but aside from age, race, and a family history of the disease, little is known about the risk factors or underlying molecular defects that cause prostate cancer. It is clear, however, that both genetic and environmental factors are involved in the etiology of this complex disease. Genetic studies are focused on identification of rare, high-penetrant hereditary prostate cancer genes and more frequent genetic polymorphisms thought to account for a higher proportion of the disease in the population and to be involved in gene-environment interactions. Toward the latter focus, the proposed study will investigate polymorphism in three genes involved in prostatic cell proliferation: insulin-like growth factor-1 (IGF-1), androgen receptor (AR), and vitamin D (VDR). Constitutional DNA will be used to genotype prostate cancer cases (n=648) and controls (n=571) to test the following hypotheses: 1) Heterozygosity for a CA repeat in the IGF-1 gene is associated with increased risk; 2) Short polyglutamine (CAG)n repeats in the AR gene are associated with enhanced risk; 3) Short polyglycine (GGN)n repeats in the AR gene are associated with enhanced risk; 4) Long poly-A alleles in the VDR gene are associated with increased risk; and 5) Homozygosity for the b allele in the VDR BsmI polymorphism is associated with elevated risk. Stored blood samples from a population-based case-control study of prostate cancer are available for the proposed study. Logistic regression will be used to estimate the relative risk of prostate cancer associated with each genotype. Data on host and environmental factors will be utilized to assess whether the strength of the associations with genotype vary by other factors such as family history or dietary fat intake. Plasma IGF-1 will be measured in controls to assess correlations between IGF-1 levels and IGF-1 genotype, and host and environmental exposures. The proposed study may provide clues on molecular markers that identify men at high risk of prostate cancer, increase our knowledge of the molecular biology of this disease, and identify new approaches to prostate cancer prevention.